One of the most crucial challenges in dementia research today is to determine which regions of the brain are vulnerable prior to the development of Alzheimer's disease (AD). This knowledge will lead to new treatment approaches to slow the progression of AD. This PPG component is a continuation of our previous studies aimed at understanding the well established galanin (GAL) remodeling response that is associated with surviving cholinergic basal forebrain (CBF) neurons in end stage AD. This is based, in part, on data derived from hippocampal slice preparations indicating that GAL inhibits acetylcholine (Ach) production (43). Recent findings have led us to hypothesize that increased GAL immunoreactivity (-ir) may be, in fact, neuroprotective for CBF neurons early in the development of dementia. This is based on the following: First, GAL-ir fibers hyperinnervate survivor CBF neurons, those that appear viable and usually do not demonstrate neurofibrillary degeneration. Second, neural degeneration is least in the anterior CBF (107) where GAL hyperinnervation occurs most (18,19). In contrast, CBF degeneration is great in the posterior CBF (107) where GAL-ir is least (104). Third, the loss of cholinergic neurons is minimal in people with mild cognitive impairment (MCI) without dementia and mild AD (5) at a point in the disease process where GAL-ir fibers begin to be over- expressed (see Preliminary data). Fourth, there is a 35% reduction in cholinergic neurons in the anterior CBF in mice lacking the GAL gene (117). These findings are consistent with the hypothesis that GAL has beneficial neuroprotective effects upon CBF neurons during the progression of AD. In the present proposal, we will test a series of hypotheses that during the transition from no cognitive impairment (NCI) to MCI to mild AD that 1) GAL over expression alters the genetic finger print of anterior CBF neurons using the novel aRNA single cell amplification technique, 2) that there is an increase in galaninergic synaptic-like appositions upon remaining anterior cholinergic neurons within the nucleus basalis using confocal laser microscopy, 3) that GAL receptor expression is increased upon anterior CBF neurons and 4) that GAL receptor expression is increased within the entorhinal cortex complex a region that plays a crucial role in the transfer of memory related information from the cortex to the hippocampus (126). The entorhinal cortex is innervated by the nucleus basalis (98a) and exhibits several degeneration early in AD (125,37,38,75,76). Galaninergic alterations will be evaluated in individuals derived from the Rush Religious Orders Study (ROS) which consists of people with NCI, MCI, mild, moderate and severe AD. The molecular, synaptic and pharmacological findings derived from these studies will be correlated with behavioral measures associated with cholinergic and entorhinal function such as declarative and working memory as well as tests of attention. These investigations may lead to novel pharmacological treatment approaches that will allow of the progression of cognitive decline seen in AD.